We hypothesize that there is a convergence of prosurvival, angiogenesis and motility signals at common pathways in the local tumor microenvironment for therapeutic targeting and monitoring. Our findings suggest that molecular therapeutics targeted against the tumor microenvironment may to be more active when administered to inhibit pathways in series rather than in parallel and also when they affect both the tumor and the local interactive cells. Aim 1) Initiation and execution of a novel statistically based predictive drug modeling project investigating drug effects on the tumor and its microenvironment. The primary approach to preclinical and clinical development is generally empiric selection of combinations, such as our successful findings with sorafenib and bevacizumab. However, we hypothesized that focused combinatorial studies using clinical available agents can yield combination therapy approaches to examine in the clinic, some of which may not be intuitively selected. We have applied optimized relative high throughput assays to a set of 4 ovarian cancer cell lines and 7 targeted agents that are in or near clinical investigation. Reverse phase proteomic array was applied to lysates of treated ovarian cancer cells. Partial least squares statistical analysis of the combined proteomic and phenotypic data is ongoing and models being developed for validation and to lead to subsequent clinical investigation. Confirmation of success of this pilot project will lead to a more comprehensive examination of agents and shRNA against their primary and potential key targets such that the biochemical cause of activity is identified. These data will be applied to xenograft models and then move into clinical trial development; the laboratory target results will become the endpoints for illustration of mechanism in the trials and, potentially later, as putative predictive biomarkers. This project was the basis for an ASCO Young Investigator Award received by Dr. John Hays, allowing him to hire and mentor a postbaccalaureate fellow. This project will continue collaboratively as Dr. Hays leaves for his first academic posting, at the James Cancer Center, OSU. 2) Our findings of the interactive role of PARP inhibition with angiogenesis inhibition was initiated based upon findings that gH2AX was required for overcoming endothelial cell hypoxic drive. We observed an interaction of a pan-VEGFR inhibitor, cediranib, with a PARP inhibitor and demonstrated a sequence specificity to administration. Further examination of the mechanisms underlying this are on hold due to resource limitations, although the clinical trial is in progress with our group responsible for translational endpoints.